EP1613294B1 - Zusammensetzungen und verwendung von peptiden und deren derivate als hemmer der oxidativen schädigung der haut - Google Patents

Zusammensetzungen und verwendung von peptiden und deren derivate als hemmer der oxidativen schädigung der haut Download PDF

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Publication number
EP1613294B1
EP1613294B1 EP04726735A EP04726735A EP1613294B1 EP 1613294 B1 EP1613294 B1 EP 1613294B1 EP 04726735 A EP04726735 A EP 04726735A EP 04726735 A EP04726735 A EP 04726735A EP 1613294 B1 EP1613294 B1 EP 1613294B1
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Prior art keywords
tyr
skin
oxidative
parfum
aldehydes
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Expired - Lifetime
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EP04726735A
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English (en)
French (fr)
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EP1613294A2 (de
Inventor
Adriano Ghirardini
Milla Ceroni
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Bottega Verde Srl
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Bottega Verde Srl
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/04—Chelating agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present invention relates to the utilization of compounds of peptidic nature as inhibitors and preventive agents of oxidative-induced degradation phenomena, as well as the use of the above compounds in the inhibition/prevention of degenerative/degradation processes induced by the reactive intermediate such as aldehydes and keto-aldehydes arising from the oxidation of endogenous and exogenous lipids, sugars and proteins.
  • the present invention also relates to the preparation of functionalised derivatives of the said peptidic compounds and their use for the same purpose, as well as to the process for their preparation and their use, alone or in combination, for cosmetic, pharmaceutical and nutritional purposes.
  • oxidative stress plays an important role in the onset and propagation of many chronic degenerative pathologies [ Esterbauer H., Schaur R.J., Zollner H.; Free Rad. Biol. Med., ,11, 81-128, 1991 ], and that the peroxidation of endogenous lipids, sugars and proteins, due to a variety of oxidative stress (chemical, physical or biological), gives rise to a burst of carbonylic species among which 4-hydroxy-2-nonenal, acrolein, crotonaldehyde, nonenal, glyoxal, methyl glyoxal and malonyl-di-aldehyde.
  • aldehydes and keto-aldehydes are formed in human body due to oxidative stress, and these degradation products contribute to different patho-physiological processes: cardiovascular diseases including atherosclerosis and long-term complications of diabetes, muscular dystrophy, rheumatoid arthritis, actinic elastosis, aging and neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and cerebral ischemia) [ Uchida K, Free Radic Biol Med, 28(12):1685-96, 2000 ; Picklo MJ, Montine TJ, Amarnath V, et al. Toxicol Appl Pharmacol, 184(3):187-97, 2002 ].
  • cardiovascular diseases including atherosclerosis and long-term complications of diabetes, muscular dystrophy, rheumatoid arthritis, actinic elastosis, aging and neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and cerebral ischemia)
  • Uchida K Free
  • seed oils may contain a significant amount of saturated and unsaturated aldehydes, such as hexanal, hexa-dienal, acrolein and these can be mutagenic after ingestion [ Grootveld M, Atherton MD, Sheerin AN, Hawkes J, Blake DR, Richens TE, Silwood CJ, Lynch E, Claxson AW.
  • the first object of the present invention relates to the use of dipeptides selected from H-His-Tyr-OH and/or H-Tyr-His-OH and/or N-acyl derivatives of the Tyr part of H-Tyr-His-OH, said acyl group having the formula -CO-(CH 2 -) n CH 3 wherein n is from 0 to 18, for the manufacture of a medicament or a cosmetic product for the inhibition/prevention of the oxidative damage of the skin, particularly for the damage of the skin due to intrinsic- or photo- aging of the skin or due to physical (UV, vis IR radiations), thermal and mechanical stress of the skin.
  • Dipeptide H-His-Tyr-OH has the following structure A: Dipeptide H-Tyr-His-OH has the following structure B
  • the biological activity of the dipeptides has been determined by the Applicant, according to the following procedures. This represents the first objective of the present invention.
  • HNE 4-hydroxy-trans-nonenal
  • a homogeneous phase model was first used to evaluate the ability of H-His-Tyr-OH and H-Tyr-His-OH to react and deactivate the cytotoxic agent HNE ( quenching activity).
  • HNE quenching activity
  • the di-peptides were incubated at 37°C in a phosphate buffer, 10 mM pH 7.4, in the presence of 200 ⁇ M HNE.
  • HNE consumption was determined after 1 hour and 24 hours of incubation by HPLC analysis, under the following experimental conditions: HP1050 (Hewlett Packard, Milano, Italy) equipped with a quaternary pump, self-sampling, on-line degasser, UV/VIS photodiode detector.
  • the separations were performed by means of a Supelco LC18 column (25 cm x 4.6 mm i.d.; particle size 5 ⁇ m) and an isocratic elution system: 60% of phase A (H 2 O/CH 3 CN/HCOOH 90/1.0/0.] v/v/v) and 40% of phase B (H 2 O/CH 3 CN 10/90 v/v/v).
  • the flow rate was maintained at 1 ml/min and the length of the revealing wave was fixed at 223 nm.
  • the values are expressed as the average ⁇ S.D of 4 determinations.
  • the quenching mechanism was established by characterization of the reaction products by mass spectrometry using an Ion Trap mass spectrometer (Thermo Finnigan LCQ Advantage, Thermoquest, Milan, Italy) equipped with an Electro-spray (ESI) ionization source.
  • the capillary temperature was maintained at 250°C and the ionization voltage at 5 kV; nitrogen at a flow rate of 0.5 1/min was used as nebulizing gas.
  • the spectra were recorded in negative and positive ion modes, at a scanning rate of 0.5 scan/sec and within a mass range of between 100 and 1000 m/z.
  • the instrumental parameters were optimised using LCQ-Xcalibur software.
  • Figure 1 shows the mass spectrum (positive ion mode) of the reaction mixture containing H-His-Tyr-OH and HNE.
  • the mass spectrum is characterized by the protonated molecular ion at m/z 319 relative to unreacted di-peptide substrate, and by the ions at m/z 475 and m/z 497, which can be attributed to the molecular ion and to the sodium adduct of the reaction product.
  • H-His-Tyr-OH and H-Tyr-His-OH were subsequently evaluated in a cellular model, using keratinocytes (NCTC 2544 human cell line, Flow Laboratories, Irvine, UK).
  • Keratinocytes were cultured, at a constant temperature of 37 ⁇ 0.1°C in a humidified 5% CO 2 atmosphere, in DMEM Dulbecco's Modified Eagle's Medium) supplemented with 10% fetal calf serum, 2 mM L-glutamine and antibiotics (100 U/ml penicillin and 0.1 mg/ml streptomycin) until 80-90% confluence as previously described ( M. Carini et al., II Farmaco 55, 526-534, 2000 )
  • H-His-Tyr-OH and H-Tyr-His-OH were demonstrated using the fluorimetric assay of Cao et al. [Free Radio Biol Med, 14(3):303-11, 1993 ], which deals with the oxidation of the fluorescent substrate R-Phicoerytrine (RPE) by peroxyl radicals generated by the radical initiator AAPH. The amount of RPE oxidation is determined by fluorimetric analysis and the results are expressed as Trolox equivalents (reference compound).
  • the values are the average ⁇ S.D of 4 determination
  • H-His-Tyr-OH and H-Tyr-His-OH antioxidant activity was subsequently devaluated in a cellular model using human kcratinocytcs cell line (NCTC 2544 human cell line, Flow Laboratories, Irvine, UK), subjected to oxidative damage induced by a flux of peroxyl radicals generated by the radical initiator 2,2'-azobis(2-aminopropane) dihydrochloride (AAPH).
  • NCTC 2544 human cell line Flow Laboratories, Irvine, UK
  • mitochondrial functionality as an index of cell viability (MTT assay)
  • cellular morphology phase contrast microscopic examinations
  • lipid peroxidation using 4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diazo- s -indacene-3-undecanoic acid(BODIPY 581/591) as membrane fluorescent probe [ Pap et al, FEBS Lett. 453:278-282, 1999 ].
  • a dramatic cytotoxic effect was observed after 6 hours exposure to 40 mM AAPH( fig.5 ).
  • the morphological examination shows cellular necrosis, concomitant to a reduced mitochondrial functionality (45 ⁇ 3.2 vs 95.6 ⁇ 2.1%; p ⁇ 0.001), and to a massive lipid peroxidation process (peroxidation index: 0.743 ⁇ 0.021 vs 0.01 ⁇ 0.005; p ⁇ 0.001).
  • the addition of H-His-Tyr-OH to the incubation medium causes a significant and dose-dependent cell protection, which is significant for all the parameters considered, already at 0.5 mM, with a total protection at 10 mM ( fig. 5 ).
  • transition metals i.e iron and copper
  • transition metals are able to catalyse free radical-mediated oxidation, according to a Fenton-like mechanism, of easily oxidizable substrates, lipids, proteins, and sugars. These reactions can take place in different sites of human body, as well as in cosmetic and food matrices.
  • the skin epidermis /derma
  • transition metals can localize and concentrate in a significant extent following different physicochemical stimulations (i.e UVB stress).
  • a metal-catalyzed oxidative degradation which involves the basic constituents of the extracellular matrix such as collagen, elastin and jaluronic acid, leads to the onset of accelerated skin aging process.
  • the second important object of the present invention deals with the design/discovery of new compounds obtained by suitable functionalization of dipeptides A. and B., which arc equipotent as antioxidant/quencher to the parent molecules.
  • the reaction scheme involves the preparation of 3-(4-tert-butoxyphenyl)-2-hexadecanoyl amino propionic acid ( II ) by reaction of 2-amino-3-(4-tert-butoxyphenyl) propionic acid ( I ) with palmitoyl chloride; functionalization of the carboxylic residue with N-hydroxysuccinimide to give compound III ; formation of the carboamide V derivative by reaction of compound III with the iso-butyl ester of L-histidine ( IV ); de-protection of the carboxylic function by alkaline hydrolysis ( VI ), subsequent de-protection of the phenolic function (acid hydrolysis by treatment with trifluoroacetic acid; TFA) to give 2-[2-hexadecanoylamino-3-(4-hydroxyphenyl)-propionyl amino]3-(3H-4-yl)-propionic acid ( VII ).
  • composition also object of the present invention, will include, as active molecule, one or more of the compounds according to the above-mentioned formulations, and also at least one of the following products: surface-active agents, emulsifiers, adhesives, preservatives, gel agents, water, solvents, inorganic excipients, lubricants, binders and stabilizers.
  • surface-active agents emulsifiers
  • emulsifiers emulsifiers
  • adhesives emulsifiers
  • preservatives gel agents
  • water solvents
  • inorganic excipients lubricants
  • binders and stabilizers binders and stabilizers.
  • dipeptides of the present invention can be incorporated directly and without further modification in foods, nutraceuticals, beverages by conventional techniques such as mixing, infusion, injection, blending, dispersing, emulsifying, immersion, spraying and kneading.
  • the di-peptides and the functionalized derivatives object of the present invention may be incorporated into various conventional pharmaceutical preparations, and dosage form, such as tablets, (plain and coated) for use orally, bucally or lingually, capsules (hard and soft, gelatin, with or without additional coatings, powders, granules (including effervescent granules), pellets, microparticulates, solutions (such as micellar, syrups, elixirs and drops) lozenges, pastilles, ampoules, emulsions, microemulsions, ointments, creams, suppositories, gels, transdermal patches, and modified release dosage forms together with customary excipients and/or diluents and stabilizers.
  • tablets plain and coated
  • bucally or lingually capsules (hard and soft, gelatin, with or without additional coatings, powders, granules (including effervescent granules), pellets, microparticulates, solutions
  • HIS-TYR The active principle is represented by the following abbreviation: HIS-TYR
  • SQUALENE 30 2.
  • CALENDULA OFFICINALIS 10 3.
  • AVOCADO OIL 10 4.
  • CAPRYLIC/CAPRIC TRIGLYCERIDE 49 5.
  • HIS-TYR 0.5 6.
  • CETEARYL GLUCOSIDE CETEARYL ALCOHOL 5
  • GLYCERYL STEARATE 1,5 3.
  • DECYL OLEATE 2 4.
  • ORYZANOL 1.
  • PRUNUS DULCIS 5 7.
  • TOCOPHERYL ACETATE 1 8.
  • DIMETHICONE 0.5
  • OLEAEUROPAEA 3 10. PRESERVED WATER q.s. to 100 % 11.
  • GLYCERIN 3 12. HIS-TYR 0.5 13.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Toxicology (AREA)
  • Dermatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Cosmetics (AREA)
  • Peptides Or Proteins (AREA)

Claims (6)

  1. Verwendung von Dipeptiden ausgewählt aus H-His-Tyr-OH und/oder H-Tyr-His-OH und/oder N-Acyl-Derivaten des Tyr-Teils von H-Tyr-His-OH, wobei die Acylgruppe die Formel -CO-(-CH2)n-CH3, worin n von 0 bis 18 ist, aufweist, zur Herstellung eines Medikaments oder eines Kosmetikprodukts zur Inhibierung/Verhinderung der oxidativen Schädigung der Haut.
  2. Verwendung nach Anspruch 1, wobei die Schädigung der Haut auf intrinsisches Altern oder Lichtalterung zurückzuführen ist.
  3. Verwendung nach Anspruch 1, wobei die Schädigung der Haut auf eine physikalische (UV-,VIS-, IR-Strahlung), thermische und mechanische Beanspruchung der Haut zurückzuführen ist.
  4. Verwendung nach Anspruch 1, wobei das Medikament oder das Kosmetikprodukt formuliert ist als Lösung, tensidhaltige Suspension, Gel, wässrige Paste, Gel-Emulsion, O/W Emulsion, W/O-Emulsion, wasserfreies Lipidsystem.
  5. N-Acyl-Derivate des Tyr-Teils von H-Tyr-His-OH, wobei die Acylgruppe die Formel -CO-(CH2)n-CH3 aufweist, worin n von 0 bis 18 ist.
  6. N-Acyl-Verbindung nach Anspruch 5, worin n =14.
EP04726735A 2003-04-11 2004-04-09 Zusammensetzungen und verwendung von peptiden und deren derivate als hemmer der oxidativen schädigung der haut Expired - Lifetime EP1613294B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000755A ITMI20030755A1 (it) 2003-04-11 2003-04-11 Peptidi e loro derivati quali inibitori di fenomeni degradativi e composizioni contenenti gli stessi.
PCT/IT2004/000199 WO2004089354A2 (en) 2003-04-11 2004-04-09 Peptides and derivatives thereof as inhibitors of oxidative-induced degradation phenomena and compositions containing them

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EP1613294A2 EP1613294A2 (de) 2006-01-11
EP1613294B1 true EP1613294B1 (de) 2009-03-11

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EP04726735A Expired - Lifetime EP1613294B1 (de) 2003-04-11 2004-04-09 Zusammensetzungen und verwendung von peptiden und deren derivate als hemmer der oxidativen schädigung der haut

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EP (1) EP1613294B1 (de)
AT (1) ATE424840T1 (de)
DE (1) DE602004019899D1 (de)
IT (1) ITMI20030755A1 (de)
WO (1) WO2004089354A2 (de)

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* Cited by examiner, † Cited by third party
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BE1016329A3 (nl) * 2004-11-22 2006-08-01 Nannic Internat Bvba Deodoriserend douche schuim.
EP3844171A4 (de) * 2018-08-31 2022-08-10 Texas Tech University System Verstärker der neurolysinaktivität

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* Cited by examiner, † Cited by third party
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US4569794A (en) * 1984-12-05 1986-02-11 Eli Lilly And Company Process for purifying proteins and compounds useful in such process
JPH06256387A (ja) * 1991-06-14 1994-09-13 Suetsuna Yoko 新規なペプチド、その製法およびそれを有効成分とする 血圧降下剤
JPH05170636A (ja) * 1991-12-25 1993-07-09 Narisu Keshohin:Kk 美白化粧料
WO1999024015A1 (en) * 1997-11-12 1999-05-20 Alza Corporation Buffered drug formulations for transdermal electrotransport delivery

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EP1613294A2 (de) 2006-01-11
WO2004089354A2 (en) 2004-10-21
ATE424840T1 (de) 2009-03-15
WO2004089354A3 (en) 2004-12-23
ITMI20030755A1 (it) 2004-10-12
DE602004019899D1 (de) 2009-04-23

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